Daily tenofovir disoproxil fumarate/emtricitabine and hydroxychloroquine for pre-exposure prophylaxis of COVID-19: a double-blind placebo-controlled randomized trial in healthcare workers

Polo, Rosa; García-Albéniz, Xabier; Rial-Crestelo, David; Garcinuño, M.A.; Toro, M. García del; Gómez-Sirvent, Juan Luís; Buzón, L; Santiago, Alberto Díaz de; Arellano, Jose Luis Pérez; Martínez-Sanz, Javier; Bachiller, P.; Alfaro, E. Martínez; Díaz-Brito, V.; Masía, Mar; Hernández-Torres, A.; Guerra, J.; Arazo, Piedad; Muñoz, L.; Arribas, José Ramón; Amo, Julia del; Moreno, Santiago; Berenguer, Juan; Martínez, Estebán; Hernán, Miguel A.; Salazar, Pablo; García-Albéniz, Xabier; Iradier, Marieta; Jarrín, Inma; Zamora, Javier; Rivero, Antonio; Menéndez, Clara; Conde, Enrique Álvarez; Montes, José L.; Terán, Carolina; Flores, Bettsy; Choque, María Elena; Peñaranda, Jhaquelin; Gorena, Gladys; Herrera, Mariluz; Farfán, Marcela; Malapeira, David Moya; Camacho, Jhonny; Ordoñez, Jovanna; Mayora, José María Pardillo; Farfán, Brayan; Morales, M.; Benítez, Maryelis; Bolaños, Rosa; Colina, Jesús; Pulido, Federico; Rubio, Rafael; Bisbal, Otilia; Lagarde, María; Epalza, Cristina; Lillo-Díaz, Cristina; Martínez, Raúl Recio; Pedrodomingo, Miguel Sebastián; Hoz, César de la; Sánchez, Demetrio López; Antolí, Ana Cristina; Grande, C. Camarena; Astudillo, Dulce María; Deltoro, Miguel García; Chirivella, Jose Ignacio; Hita, C.; Montero, María Carmen; Ruíz, Juan Carlos; Alonso, Ma Mar; Alemán, Ma Remedios; López, Ana M.; García, Dácil; Pelazas, Ricardo; Recio, Pablo González; Martínez-Vera, Fernando; Reyes, Alejandro; Fuente, Sara de la; Muñoz, A.; Vázquez, José Manuel; Carranza, Cristina; Hernández, Michele; Jaén, Nieves; Lavilla, Carmen; Pisos, Elena; Suárez, Laura; Santos, Ignacio; García‐Fraile, Lucio; Gutiérrez, Ángela; Bautista, Azucena; Muñoz, Sara; Santos, J.; Ferreira, Eva Maria Luiz; Carrero, Ana; Mateos, Fernando; Blanch, Jose; García, Julian Eloy Solis; Sanmartí, Montserrat; Barrena, Raquel; Moreno, Encarna; Álvarez, M. Carmen; García-Abellán, Javier; Gutiérrez, Félix; Padilla, Sergio; Estañ, Gabriel; Moral, Encarnación; Marı́n, Sonia; Roura, Aychel Elena; Pareja, Ana; Regidor, Manuel Martín; Gutiérrez, Esperanza; Valdivia, Luis Jorge; Capón, Patricia; Domínguez, Antonia; Moreno, Antonia Sajardo; Ruiz, Luis Fernández-Galiano; Garrido, R.; Cecilio, Álvaro; Fenoll, Rosa; Peregrina, José; Anguita, Francisco; Martin, Laura B.; Dronda, Fernando; Häemmerle, Johannes; Crespillo, Clara; Flores, Juan; Castellano, Lidia; Dueñas, Carlos; Fernández, Laura Rodríguez; Zapico, Genoveva; Tasias, María; Berrocal, Pablo Fernández; Campo, Cristina; Baño, Jesús Rodríguez; Domínguez-Castellano, Ángel; Ríos‐Villegas, Maria José; Noguera-Julián, Antoni; Fortuny, Clàudia; Ríos-Barnés, María; Hernández-Pérez, Guillermo; Sánchez-Ledesma, María; Carbonell, Cristina; Sánchez-Navarro, Jacinto; Hoyo, Cristina Sánchez del; Morán, Yolanda; Cabello, Alfonso; Carrillo, Irene; Górgolas, Miguel; Antela, Antonio; Losada, Elena; Domínguez, M. J.; Mariño, Ana; Sánchez-Trigo, Sabela; Martínez-Varela, Silvia; Aguilar, Eduardo J.; González-Lama, Jesús; Plata, Alejandro; Rubio, Ma Teresa; Marín, Marta María; Zardoya, Lucía; Mendoza, Diego de; Gutiérrez, Antonio; Coll, Rosa; Sanjoaquín, Isabel; Loscos, Silvia; Geijo, M.P.; Belinchon, O.; Bernal, Enrique; Deschamps-Perdomo, Ámbar; Arranz, J. A.; Borobia, Alberto M.; Knobel, Hernando; Artero, Arturo; Rivero, María Dolores; Galindo, Marı́a José; Cepeda, Concepción; Blanco, José Ramón; Estrada, Vicente; Lecuona, Ainhoa; Gómez, Julia Sánchez; Asensi, Vı́ctor; Cervero, Miguel

doi:10.1016/j.cmi.2022.07.006

Cited by 12 publications

(3 citation statements)

References 28 publications

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“…Since HCQ has proven to be able to prevent SARS-CoV-2 infection in vitro,31 32 a number of clinical trials and observational studies embarked on evaluating HCQ as prophylaxis to contain SARS-CoV-2 in the human body. Most of these studies reported non-significant associations between HCQ prophylaxis and reduced SARS-CoV-2 infection rate,15 19 21 33–50 while only a few reported HCQ prophylaxis could significantly decrease SARS-CoV-2 infection rate 51–59. Our findings of significant association between PrEP use of HCQ and reduced risk of SARS-CoV-2 infection in clinical trials are consistent with another meta-analysis of cohort studies among high-risk HCWs performed by Stricker and Fesler 60.…”

Section: Discussionsupporting

confidence: 87%

Repurposed drug studies on the primary prevention of SARS-CoV-2 infection during the pandemic: systematic review and meta-analysis

Zhou,

Verweij,

Bijlsma

et al. 2023

BMJ Open Resp Res

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ObjectiveCurrent evidence on the effectiveness of SARS-CoV-2 prophylaxis is inconclusive. We aimed to systematically evaluate published studies on repurposed drugs for the prevention of laboratory-confirmed SARS-CoV-2 infection and/or COVID-19 among healthy adults.DesignSystematic review.EligibilityQuantitative experimental and observational intervention studies that evaluated the effectiveness of repurposed drugs for the primary prevention of SARS-CoV-2 infection and/or COVID-19 disease.Data sourcePubMed and Embase (1 January 2020–28 September 2022).Risk of biasCochrane Risk of Bias 2.0 and Risk of Bias in Non-Randomised Studies of Interventions tools were applied to assess the quality of studies.Data analysisMeta-analyses for each eligible drug were performed if ≥2 similar study designs were available.ResultsIn all, 65 (25 trials, 40 observational) and 29 publications were eligible for review and meta-analyses, respectively. Most studies pertained to hydroxychloroquine (32), ACE inhibitor (ACEi) or angiotensin receptor blocker (ARB) (11), statin (8), and ivermectin (8). In trials, hydroxychloroquine prophylaxis reduced laboratory-confirmed SARS-CoV-2 infection (risk ratio: 0.82 (95% CI 0.74 to 0.90), I2=48%), a result largely driven by one clinical trial (weight: 60.5%). Such beneficial effects were not observed in observational studies, nor for prognostic clinical outcomes. Ivermectin did not significantly reduce the risk of SARS-CoV-2 infection (RR: 0.35 (95% CI 0.10 to 1.26), I2=96%) and findings for clinical outcomes were inconsistent. Neither ACEi or ARB were beneficial in reducing SARS-CoV-2 infection. Most of the evidence from clinical trials was of moderate quality and of lower quality in observational studies.ConclusionsResults from our analysis are insufficient to support an evidence-based repurposed drug policy for SARS-CoV-2 prophylaxis because of inconsistency. In the view of scarce supportive evidence on repurposing drugs for COVID-19, alternative strategies such as immunisation of vulnerable people are warranted to prevent the future waves of infection.PROSPERO registration numberCRD42021292797.

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Section: Discussionsupporting

confidence: 87%

Repurposed drug studies on the primary prevention of SARS-CoV-2 infection during the pandemic: systematic review and meta-analysis

Zhou,

Verweij,

Bijlsma

et al. 2023

BMJ Open Resp Res

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“…A beneficial effect of TDF for prophylaxis or early treatment of COVID-19 is compatible with the results of two randomized trials in nonhospitalized patients. In France, a phase 2 trial in 60 outpatients with early COVID-19 found lower nasopharyngeal shedding of SARS-CoV-2 after initiation of TDF/FTC [16]; in Spain and Latin America, the EPICOS trial could not rule out a beneficial effect of TDF/FTC as preexposure prophylaxis for COVID-19 among healthcare workers, but effect estimates were very imprecise because the target sample size was not met [17]. In contrast, the PANCOVID trial in hospitalized patients with COVID-19 in Spain reported no beneficial effects of TDF/FTC compared with placebo [18].…”

Section: Discussionmentioning

confidence: 99%

Tenofovir disoproxil fumarate/emtricitabine and severity of coronavirus disease 2019 in people with HIV infection

Amo

Polo

Moreno

et al. 2022

Aids

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Background: Effective, safe, and affordable antivirals are needed for coronavirus disease 2019 (COVID-19). Several lines of research suggest that tenofovir may be effective against COVID-19, but no large-scale human studies with appropriate adjustment for comorbidities have been conducted. Methods: We studied HIV-positive individuals on antiretroviral therapy (ART) in 2020 at 69 HIV clinics in Spain. We collected data on sociodemographics, ART, CD4+ cell count, HIV-RNA viral-load, comorbidities and the following outcomes: laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, COVID-19 hospitalization, intensive care unit (ICU) admission and death. We compared the 48-week risks for individuals receiving tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC), tenofovir alafenamide (TAF)/FTC, abacavir (ABC)/lamivudine (3TC), and other regimes. All estimates were adjusted for clinical and sociodemographic characteristics via inverse probability weighting. Results: Of 51 558 eligible individuals, 39.6% were on TAF/FTC, 11.9% on TDF/FTC, 26.6% on ABC/3TC, 21.8% on other regimes. There were 2402 documented SARS-CoV-2 infections (425 hospitalizations, 45 ICU admissions, 37 deaths). Compared with TAF/FTC, the estimated risk ratios (RR) (95% confidence interval) of hospitalization were 0.66 (0.43, 0.91) for TDF/FTC and 1.29 (1.02, 1.58) for ABC/3TC, the RRs of ICU admission were 0.28 (0.11, 0.90) for TDF/FTC and 1.39 (0.70, 2.80) for ABC/3TC, and the RRs of death were 0.37 (0.23, 1.90) for TDF/FTC and 2.02 (0.88–6.12) for ABC/3TC. The corresponding RRs of hospitalization for TDF/FTC were 0.49 (0.24, 0.81) in individuals ≥50 years and 1.15 (0.59, 1.93) in younger individuals. Discussion: Compared with other antiretrovirals, TDF/FTC lowers COVID-19 severity among HIV-positive individuals with virological control. This protective effect may be restricted to individuals aged 50 years and older.

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“…A phase 2 trial in 60 persons with mild COVID-19, funded by Caen University Hospital in France, found reduced nasopharyngeal shedding of SARS-CoV-2 in the TDF–FTC group ( 35 ). A double-blind, placebo-controlled randomized trial studied TDF–FTC as preexposure prophylaxis in health care workers from Spain, Bolivia, and Venezuela ( 36 ). This trial, funded by the Instituto de Salud Carlos III and led by the Ministry of Health of Spain, recruited fewer than 1000 persons (out of 4000) before vaccination started and enrollment had to be halted.…”

Section: Why Didn't Tenofovir Disoproxil Fumarate Make It Into Random...mentioning

confidence: 99%

Drug Repurposing and Observational Studies: The Case of Antivirals for the Treatment of COVID-19

Hernán

Amo

2023

Ann Intern Med

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Remdesivir and molnupiravir received emergency use authorization on the basis of single trials launched after observed in vitro activity against SARS-CoV-2. For tenofovir disoproxil fumarate (TDF), little in vitro evidence was generated, and no randomized trials for early treatment were done. Yet, observational evidence suggested a lower risk for severe COVID-19 in TDF users compared with nonusers. The authors review the decision-making process for these 3 drugs and propose better use of available observational evidence for the repurposing of drugs during public health emergencies.

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Daily tenofovir disoproxil fumarate/emtricitabine and hydroxychloroquine for pre-exposure prophylaxis of COVID-19: a double-blind placebo-controlled randomized trial in healthcare workers

Cited by 12 publications

References 28 publications

Repurposed drug studies on the primary prevention of SARS-CoV-2 infection during the pandemic: systematic review and meta-analysis

Repurposed drug studies on the primary prevention of SARS-CoV-2 infection during the pandemic: systematic review and meta-analysis

Tenofovir disoproxil fumarate/emtricitabine and severity of coronavirus disease 2019 in people with HIV infection

Drug Repurposing and Observational Studies: The Case of Antivirals for the Treatment of COVID-19

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